Assistant Professor of Biochemistry and Adjunct Assistant Professor of Nutrition and Integrative Physiology and of Pharmaceutics
and Pharmaceutical Chemistry

B.S. National Taiwan University

Ph.D. Harvard University

Molecular Biology Program

Biological Chemistry Program

Diabetes, Insulin, Peptide and Protein Therapeutics, Chemical Biology

Research

We focus on using synthetic protein engineering to create peptide or protein therapeutics
with the goals to understand their biological effects in human diseases and improve
clinical benefits in treating patients. Specifically, we use synthetic chemistry methods
to introduce unnatural moieties into native proteins and peptides to generate analogues
with enhanced properties. We are interested in tackling type 1 diabetes (T1D), an
autoimmune disease in which the pancreas stops producing insulin, a hormone that enables
glucose uptake from blood. By developing novel insulin and glucagon analogues, we
hope to maintain normal blood glucose levels in type 1 diabetic patients.

Currently, we are focusing on the following research programs:

New insulin and glucagon analogues for the use in artificial pancreas

Glucose-responsive insulin or “smart insulin”

Synthetic methodology for creating peptide and protein analogues

New insulin and glucagon analogues for the use in artificial pancreas The artificial pancreas is a technology in development to help people with diabetes
automatically control their blood glucose levels by providing the substitute endocrine
functionality (insulin and glucagon) of a healthy pancreas. A continuous glucose monitor
(CGM) senses glucose levels via a needle inserted under the skin. Based on these measurements,
a dual-hormone pump injects either insulin or glucagon to maintain normal blood glucose
levels. By automating detection of blood sugar levels and delivery of insulin/glucagon
in response to those levels, an artificial pancreas has the potential to transform
the lives of people with type 1 diabetes.

However, currently available fast-acting insulin analogues still have relatively slow
absorption after subcutaneous injection, and the poor stability of currently available
glucagon formulations necessitated daily replacement of the glucagon in the pump with
freshly reconstituted material. In our lab, we focus on developing a next-generation
ultrafast-acting insulin analogue that accelerates the insulin action and therefore
mimics the physiological insulin action. We are also interested in developing stable
glucagon analogues that stay fresh in dual-hormone pumps for at least three days.

Glucose-responsive insulin or “smart insulin” Insulin analogues, either fast-acting or long-acting, have been demonstrated to improve
glycemic control and reduce diabetes associated complications more than native insulin.
However, although currently available insulin analogues reduce blood glucose levels,
this blood glucose lowering action is not regulated in a glucose dependent fashion.
The major consequence of excess insulin administration is hypoglycemia, because currently
available injected insulin analogues remain biologically active, even when blood sugars
are falling into dangerously low levels. Hypoglycemia therefore is the rate-limiting
step in the glycemic management of diabetes. Hypoglycemia can lead to acute complications
such as loss of consciousness, coma, and even death. On the other hand, insufficient
insulin administration leads to inadequately treated diabetes that results in chronic
hyperglycemia and complications such as blindness, kidney failure, and heart disease.
There remains a need to modulate the kinetics of injected insulin therapy in vivo to more closely match the dynamics of fluctuating blood glucose levels that occur
in vivo.

We are interested in developing glucose-responsive insulin or “smart insulin” such
that its biological activity is regulated by the circulating glucose. Ideally, a “smart
insulin” is a once daily administered drug that precisely delivers the required amount
of insulin and, by responding to the circulating local glucose levels, will maintain
normal glucose levels throughout the day. An estimated 2-10% of T1D patients will
die of hypoglycemia and fear of this dire outcome prevents more aggressive blood glucose
control. Therefore, the “smart insulin” represents a paradigm shift in T1D treatment
and has the potential to improve the quality of life and save lives of T1D patients
from acute hypoglycemia.

Synthetic methodology for creating peptide and protein analogues Peptides and proteins have emerged as effective diagnostics and therapeutics in diseases
including cancers, metabolic diseases, and autoimmune diseases. Synthetically modified
peptide and protein analogues have demonstrated their potential to further enhance
the properties of the native proteins. For example, PEGylated proteins improve the
safety profile of the protein by shielding antigenic and immunogenic epitopes and
reduce metabolic degradation. Despite these successes, synthetically modified peptide
and protein derivatives remain underutilized. The complexity of protein structures
usually leads to mixtures of protein derivatives and purification of the mixture is
often challenging. A general platform for the synthesis and purification of modified
peptide and protein analogues would enable the production of valuable protein molecules
with new functions.

We aim to develop new methodology for high-throughput generation of peptide and protein
analogues with unnatural segments. This could expedite the discovery of novel functional
peptide and protein analogues and provide lead molecules for further optimization.